PDF(Pubmed)
Abstract：
In many cell types, the rise in cytosolic Ca2+ due to opening of Ca2+ release-activated Ca2+ (CRAC) channels drives a plethora of responses, including secretion, motility, energy production, and gene expression. The amplitude and time course of the cytosolic Ca2+ rise is shaped by the rates of Ca2+ entry into and removal from the cytosol. However, an extended bulk Ca2+ rise is toxic to cells. Here, we show that the plasma membrane Ca2+ ATPase (PMCA) pump plays a major role in preventing a prolonged cytosolic Ca2+ signal following CRAC channel activation. Ca2+ entry through CRAC channels leads to a sustained sub-plasmalemmal Ca2+ rise but bulk Ca2+ is kept low by the activity of PMCA4b. Despite the low cytosolic Ca2+, membrane permeability to Ca2+ is still elevated and Ca2+ continues to enter through CRAC channels. Ca2+-dependent NFAT activation, driven by Ca2+ nanodomains near the open channels, is maintained despite the return of bulk Ca2+ to near pre-stimulation levels. Our data reveal a central role for PMCA4b in determining the pattern of a functional Ca2+ signal and in sharpening local Ca2+ gradients near CRAC channels, whilst protecting cells from a toxic Ca2+ overload.
摘要：
在许多细胞类型中，由于Ca2+释放激活的Ca2+（CRAC）通道的开放，细胞溶质Ca2+的上升驱动了过多的反应，包括分泌物，运动性,能源生产，和基因表达。细胞溶质Ca2上升的幅度和时间过程由Ca2进入和从细胞溶质中去除的速率决定。然而,大量的Ca2+增加对细胞是有毒的。这里,我们表明，质膜Ca2ATPase（PMCA）泵在阻止CRAC通道激活后延长的胞浆Ca2信号中起着重要作用。Ca2通过CRAC通道进入导致持续的亚浆膜Ca2升高，但PMCA4b的活性使大量Ca2保持较低。尽管细胞溶质Ca2+较低,膜对Ca2+的通透性仍然升高,并且Ca2+继续通过CRAC通道进入。Ca2+依赖性NFAT激活，由开放通道附近的Ca2+纳米域驱动，尽管大量Ca2+恢复到接近刺激前的水平，但仍保持不变。我们的数据揭示了PMCA4b在确定功能性Ca2信号的模式和在CRAC通道附近锐化局部Ca2梯度方面的核心作用。同时保护细胞免受有毒的Ca2+过载。
